Quinoline and Quinoxaline Derivatives as Kinase Inhibitors

ABSTRACT

A series of quinoline and quinoxaline derivatives, substituted by a fused bicyclic pyridine or pyrimidine moiety attached via an alkylene chain optionally linked to a heteroatom, being selective inhibitors of P13 kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.

The present invention relates to a class of quinoline and quinoxalinederivatives, and to their use in therapy. These compounds are selectiveinhibitors of phosphoinositide 3-kinase (PI3K) enzymes, and areaccordingly of benefit as pharmaceutical agents, especially in thetreatment of adverse inflammatory, autoimmune, cardiovascular,neurodegenerative, metabolic, oncological, nociceptive and ophthalmicconditions.

The PI3K pathway is implicated in a variety of physiological andpathological functions that are believed to be operative in a range ofhuman diseases. Thus, PI3Ks provide a critical signal for cellproliferation, cell survival, membrane trafficking, glucose transport,neurite outgrowth, membrane ruffling, superoxide production, actinreorganization and chemotaxis (cf. S. Ward et al., Chemistry & Biology,2003, 10, 207-213; and S. G. Ward & P. Finan, Current Opinion inPharmacology, 2003, 3, 426-434); and are known to be involved in thepathology of cancer, and metabolic, inflammatory and cardiovasculardiseases (cf. M. P. Wymann et al., Trends in Pharmacol. Sci., 2003, 24,366-376). Aberrant upregulation of the PI3K pathway is implicated in awide variety of human cancers (cf. S. Brader & S. A. Eccles, Tumori,2004, 90, 2-8).

The compounds in accordance with the present invention, being potent andselective PI3K inhibitors, are therefore beneficial in the treatmentand/or prevention of various human ailments. These include autoimmuneand inflammatory disorders such as rheumatoid arthritis, multiplesclerosis, asthma, inflammatory bowel disease, psoriasis and transplantrejection; cardiovascular disorders including thrombosis, cardiachypertrophy, hypertension, and irregular contractility of the heart(e.g. during heart failure); neurodegenerative disorders such asAlzheimer's disease, Parkinson's disease, Huntington's disease, stroke,amyotrophic lateral sclerosis, spinal cord injury, head trauma andseizures; metabolic disorders such as obesity and type 2 diabetes;oncological conditions including leukaemia, glioblastoma, lymphoma,melanoma, and human cancers of the liver, bone, skin, brain, pancreas,lung, breast, stomach, colon, rectum, prostate, ovary and cervix; painand nociceptive disorders; and ophthalmic disorders includingage-related macular degeneration (ARMD).

In addition, the compounds in accordance with the present invention maybe beneficial as pharmacological standards for use in the development ofnew biological tests and in the search for new pharmacological agents.Thus, the compounds of this invention may be useful as radioligands inassays for detecting compounds capable of binding to human PI3K enzymes.

WO 2008/118454, WO 2008/118455 and WO 2008/118468 describe variousseries of quinoline and quinoxaline derivatives that are structurallyrelated to each other and are stated to be useful to inhibit thebiological activity of human PI3Kδ and to be of use in treatingPI3K-mediated conditions or disorders.

WO 2009/081105, copending international application PCT/GB2009/002504,published on 29 Apr. 2010 as WO 2010/046639 (claiming priority fromUnited Kingdom patent application 0819593.5), copending internationalapplication PCT/GB2010/000243, published on 19 Aug. 2010 as WO2010/092340 (claiming priority from United Kingdom patent applications0902450.6 and 0914533.5), copending international applicationPCT/GB2010/000361, published on 10 Sep. 2010 as WO 2010/100405 (claimingpriority from United Kingdom patent applications 0903949.6 and0915586.2), and copending international application PCT/GB2010/001000(claiming priority from United Kingdom patent application 0908957.4)describe separate classes of fused bicyclic heteroaryl derivatives asselective inhibitors of PI3K enzymes that are of benefit in thetreatment of adverse inflammatory, autoimmune, cardiovascular,neurodegenerative, metabolic, oncological, nociceptive and ophthalmicconditions.

None of the prior art available to date, however, discloses or suggeststhe precise structural class of quinoline and quinoxaline derivatives asprovided by the present invention.

The compounds of the present invention are potent and selective PI3Kinhibitors having a binding affinity (IC₅₀) for the human PI3Kα and/orPI3Kβ and/or PI3Kγ and/or PI3Kδ isoform of 50 μM or less, generally of20 μM or less, usually of 5 μM or less, typically of 1 μM or less,suitably of 500 nM or less, ideally of 100 nM or less, and preferably of20 nM or less (the skilled person will appreciate that a lower IC₅₀figure denotes a more active compound). The compounds of the inventionmay possess at least a 10-fold selective affinity, typically at least a20-fold selective affinity, suitably at least a 50-fold selectiveaffinity, and ideally at least a 100-fold selective affinity, for thehuman PI3Kα and/or PI31β and/or PI3Kγ and/or PI3Kδ isoform relative toother human kinases.

The present invention provides a compound of formula (IA) or (IB) or anN-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof:

wherein

V represents O or S;

Y represents N or C—R⁶;

X represents N or C—R⁷;

E represents an optionally substituted straight or branched C₁₋₄alkylene chain;

Q represents oxygen, sulfur, N—R⁸ or a covalent bond;

M represents the residue of an optionally substituted saturated five-,six- or seven-membered monocyclic ring containing one nitrogen atom and0, 1, 2 or 3 additional heteroatoms independently selected from N, O andS, but containing no more than one O or S atom;

W represents C—R⁹ or N;

R¹, R² and R³ independently represent hydrogen, halogen, cyano, nitro,C₁₋₆ alkyl, trifluoromethyl, aryl(C₁₋₆)alkyl, hydroxy, C₁₋₆ alkoxy,difluoromethoxy, trifluoromethoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl,C₁₋₆ alkylsulfonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkyl-amino, C₂₋₆alkylcarbonylamino, C₂₋₆ alkoxycarbonylamino, C₁₋₆ alkylsulfonylamino,formyl, C₂₋₆ alkylcarbonyl, carboxy, C₂₋₆ alkoxycarbonyl, aminocarbonyl,C₁₋₆ alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, aminosulfonyl, C₁₋₆alkylaminosulfonyl or di(C₁₋₆)alkylaminosulfonyl;

R⁴ represents C₁₋₆ alkyl, aryl, aryl(C₁₋₆)alkyl, heteroaryl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substitutedby one or more substituents; or hydrogen, halogen, trifluoromethyl,—OR^(a), —SR^(a), —SOR^(a), —SO₂R^(a), —NR^(b)R^(c), —NR^(c)COR^(d),—NR^(c)CO₂R^(d), —NR^(c)SO₂R^(e), —COR^(d), —CO₂R^(d), —CONR^(b)R^(c) or—SO₂NR^(b)R^(c);

R⁵ and R⁶ independently represent C₁₋₆ alkyl, aryl, aryl(C₁₋₆)alkyl,heteroaryl or heteroaryl(C₁₋₆)alkyl, any of which groups may beoptionally substituted by one or more substituents; or hydrogen,halogen, trifluoromethyl, —OR^(a), —SR^(a), —SOR^(a), —SO₂R^(a),—NR^(b)R^(c), —NR^(c)COR^(d), —NR^(c)CO₂R^(d), —NR^(c)SO₂R^(e),—COR^(d), —CO₂R^(d), —CONR^(b)R^(c) or —SO₂NR^(b)R^(c); or

R⁵ and R⁶, when taken together with the carbon atoms to which they areattached, represent optionally substituted C₅₋₇ cycloalkenyl;

R⁷ represents C₁₋₆ alkyl, aryl, aryl(C₁₋₆)alkyl, heteroaryl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substitutedby one or more substituents; or hydrogen, halogen, trifluoromethyl,—OR^(a), —SR^(a), —SOR^(a), —SO₂R^(a), —NR^(b)R^(c), —NR^(c)COR^(d),—NR^(c)CO₂R^(d), —NR^(c)SO₂R^(e), —COR^(d), —CO₂R^(d), —CONR^(b)R^(c) or—SO₂NR^(b)R^(c);

R⁸ represents hydrogen or C₁₋₆ alkyl;

R⁹ represents hydrogen, halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy;

R^(a) represents C₁₋₆ alkyl, difluoromethyl or trifluoromethyl;

R^(b) represents hydrogen or trifluoromethyl; or C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, C₃₋₇heterocycloalkyl, C₃₋₇ heterocycloalkyl-(C₁₋₆)alkyl, heteroaryl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substitutedby one or more substituents;

R^(c) represents hydrogen, C₁₋₆ alkyl or C₃₋₇ cycloalkyl;

R^(d) represents hydrogen or C₁₋₆ alkyl; and

R^(e) represents C₁₋₆ alkyl.

Where any of the groups in the compounds of formula (IA) and (IB) aboveis stated to be optionally substituted, this group may be unsubstituted,or substituted by one or more substituents. Typically, such groups willbe unsubstituted, or substituted by one or two substituents.

For use in medicine, the salts of the compounds of formula (IA) and (IB)will be pharmaceutically acceptable salts. Other salts may, however, beuseful in the preparation of the compounds of the invention or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundof the invention with a solution of a pharmaceutically acceptable acidsuch as hydrochloric acid, sulphuric acid, methanesulphonic acid,fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid,citric acid, tartaric acid or phosphoric acid. Furthermore, where thecompounds of the invention carry an acidic moiety, e.g. carboxy,suitable pharmaceutically acceptable salts thereof may include alkalimetal salts, e.g. sodium or potassium salts; alkaline earth metal salts,e.g. calcium or magnesium salts; and salts formed with suitable organicligands, e.g. quaternary ammonium salts.

The present invention includes within its scope solvates of thecompounds of formula (IA) and (IB) above. Such solvates may be formedwith common organic solvents, e.g. hydrocarbon solvents such as benzeneor toluene; chlorinated solvents such as chloroform or dichloromethane;alcoholic solvents such as methanol, ethanol or isopropanol; etherealsolvents such as diethyl ether or tetrahydrofuran; or ester solventssuch as ethyl acetate. Alternatively, the solvates of the compounds offormula (IA) and (IB) may be formed with water, in which case they willbe hydrates.

Suitable alkyl groups which may be present on the compounds of theinvention include straight-chained and branched C₁₋₆ alkyl groups, forexample C₁₋₄ alkyl groups. Typical examples include methyl and ethylgroups, and straight-chained or branched propyl, butyl and pentylgroups. Particular alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyland 3-methylbutyl. Derived expressions such as “C₁₋₆ alkoxy”, “C₁₋₆alkylthio”, “C₁₋₆ alkylsulphonyl” and “C₁₋₆ alkylamino” are to beconstrued accordingly.

The expression “C₁₋₃ alkylene chain” refers to a divalent straight orbranched alkylene chain containing 1 to 3 carbon atoms. Typical examplesinclude methylene, ethylene, methylmethylene, ethylmethylene anddimethylmethylene.

Specific C₃₋₇ cycloalkyl groups are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

Suitable aryl(C₁₋₆)alkyl groups include benzyl, phenylethyl,phenylpropyl and naphthylmethyl.

Suitable heterocycloalkyl groups, which may comprise benzo-fusedanalogues thereof, include azetidinyl, tetrahydrofuranyl,dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl,imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,piperazinyl, 1,2,3,4-tetrahydro-quinoxalinyl, homopiperazinyl,morpholinyl, benzoxazinyl and thiomorpholinyl.

Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl,thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolyl,pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl,oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl,isothiazolyl, imidazolyl, benzimidazolyl, imidazo[1,2-c]pyridinyl,imidazo[4,5-b]pyridinyl, purinyl, imidazo[1,2-a]pyrimidinyl,imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl,benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl,naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl,quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl andchromenyl groups.

The term “halogen” as used herein is intended to include fluorine,chlorine, bromine and iodine atoms, typically fluorine, chlorine orbromine.

Where the compounds of formula (IA) and (IB) have one or more asymmetriccentres, they may accordingly exist as enantiomers. Where the compoundsof the invention possess two or more asymmetric centres, they mayadditionally exist as diastereomers. The invention is to be understoodto extend to all such enantiomers and diastereomers, and to mixturesthereof in any proportion, including racemates. Formula (IA) and (IB)and the formulae depicted hereinafter are intended to represent allindividual stereoisomers and all possible mixtures thereof; unlessstated or shown otherwise. In addition, compounds of formula (IA) and(IB) may exist as tautomers, for example keto (CH₂C═O)

enol (CH═CHOH) tautomers or amide (NHC═O)

hydroxyimine (N═COH) tautomers. Formula (IA) and (IB) and the formulaedepicted hereinafter are intended to represent all individual tautomersand all possible mixtures thereof; unless stated or shown otherwise.

It is to be understood that each individual atom present in formula (IA)and (IB), or in the formulae depicted hereinafter, may in fact bepresent in the form of any of its naturally occurring isotopes, with themost abundant isotope(s) being preferred. Thus, by way of example, eachindividual hydrogen atom present in formula (IA) and (IB), or in theformulae depicted hereinafter, may be present as a ¹H, ²H (deuterium) or³H (tritium) atom, preferably ¹H. Similarly, by way of example, eachindividual carbon atom present in formula (IA) and (IB), or in theformulae depicted hereinafter, may be present as a ¹²C, ¹³C or ¹⁴C atom,preferably ¹²C.

In one embodiment, V represents O. In another embodiment, V representsS.

In one embodiment, Y represents N. In another embodiment, Y representsC—R⁶.

In one embodiment, X represents N. In another embodiment, X representsC—R⁷.

In one embodiment, W represents C—R⁹. In another embodiment, Wrepresents N.

Specific sub-classes of compounds in accordance with the presentinvention are represented by the compounds of formula (IA-1), (IA-2),(IB-1) and (IB-2), especially (IA-1) and (IB-1):

wherein V, Y, X, E, Q, M, R¹, R², R³, R⁴, R⁵ and R⁹ are as definedabove.

Typical values of E include methylene (—CH₂—), (methyl)methylene,ethylene (—CH₂CH₂—), (ethyl)methylene, (dimethyl)methylene,(methyl)ethylene, (propyl)methylene and (dimethyl)ethylene, any of whichchains may be optionally substituted by one or more substituents.Suitably, such chains are unsubstituted, monosubstituted ordisubstituted. Preferably, such chains are unsubstituted ormonosubstituted. In one embodiment, such chains are unsubstituted. Inanother embodiment, such chains are monosubstituted.

Examples of suitable substituents on the alkylene chain represented by Einclude trifluoromethyl, C₃₋₇ heterocycloalkyl, aryl, oxo, hydroxy, C₁₋₆alkoxy, C₂₋₆ alkoxy-carbonyl(C₁₋₆)alkoxy, aminocarbonyl(C₁₋₆)alkoxy,trifluoromethoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,aminocarbonyl, C₁₋₆ alkylaminocarbonyl and di(C₁₋₆)alkylaminocarbonyl.

Examples of particular substituents on the alkylene chain represented byE include trifluoromethyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, phenyl, oxo, hydroxy, ethoxy, ethoxycarbonylmethoxy,aminocarbonylmethoxy, trifluoromethoxy, amino, methylamino,dimethylamino, aminocarbonyl, methylaminocarbonyl anddimethylamino-carbonyl.

Suitable values of E include methylene (—CH₂—) and (methyl)methylene.

A particular value of E is (methyl)methylene, i.e. —CH(CH₃)—.

Another value of E is methylene, i.e. —CH₂—.

Suitable values of Q include oxygen and N—R⁸.

In one embodiment, Q represents oxygen. In another embodiment, Qrepresents sulfur. In a further embodiment, Q represents N—R⁸. In astill further embodiment, Q represents a covalent bond.

In one embodiment, M represents the residue of an optionally substitutedsaturated five-membered monocyclic ring. In another embodiment, Mrepresents the residue of an optionally substituted saturatedsix-membered monocyclic ring. In a further embodiment, M represents theresidue of an optionally substituted saturated seven-membered monocyclicring.

In one embodiment, the monocyclic ring of which M is the residuecontains one nitrogen atom and no additional heteroatoms (i.e. it is anoptionally substituted pyrrolidin-1-yl, piperidin-1-yl orhexahydroazepin-1-yl ring). In another embodiment, the monocyclic ringof which M is the residue contains one nitrogen atom and one additionalheteroatom selected from N, O and S. In a further embodiment, themonocyclic ring of which M is the residue contains one nitrogen atom andtwo additional heteroatoms selected from N, O and S, of which not morethan one is O or S. In a still further embodiment, the monocyclic ringof which M is the residue contains one nitrogen atom and threeadditional heteroatoms selected from N, O and S, of which not more thanone is O or S.

Suitable values of the monocyclic ring of which M is the residue includepyrrolidin-1-yl, imidazolidin-1-yl, piperidin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, piperazin-1-yl and [1,4]diazepan-1-yl, any of whichrings may be optionally substituted by one or more substituents.

Selected values of the monocyclic ring of which M is the residue includepyrrolidin-1-yl, piperidin-1-yl and piperazin-1-yl, any of which ringsmay be optionally substituted by one or more substituents.

A particular value of the monocyclic ring of which M is the residue isoptionally substituted piperazin-1-yl.

In one embodiment, the monocyclic ring of which M is the residue isunsubstituted. In another embodiment, the monocyclic ring of which M isthe residue is substituted by one or more substituents. In one subset ofthat embodiment, the monocyclic ring of which M is the residue ismonosubstituted. In another subset of that embodiment, the monocyclicring of which M is the residue is disubstituted.

Typical examples of suitable substituents on the monocyclic ring ofwhich M is the residue include halogen, C₁₋₆ alkyl, heteroaryl, C₁₋₆alkoxy, difluoromethoxy, trifluoromethoxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulphonyl, hydroxy, hydroxy(C₁₋₆)alkyl, cyano,trifluoromethyl, oxo, C₂₋₆ alkylcarbonyl, (C₃₋₇)cycloalkyl-carbonyl,(C₃₋₇)heterocycloalkylcarbonyl(C₁₋₆)alkyl, carboxy, carboxy(C₁₋₆)alkyl,C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, amino,amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, phenylamino,pyridinylamino, C₂₋₆ alkylcarbonylamino,hydroxy-(C₁₋₆)alkylcarbonylamino, (C₃₋₇)cycloalkylcarbonylamino, C₂₋₆alkoxycarbonylamino, C₁₋₆ alkylsulphonylamino, aminocarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆)alkylamino-carbonyl anddi(C₁₋₆)alkylaminocarbonyl(C₁₋₆)alkyl. Additional examples includehydroxy(C₁₋₆)alkylcarbonyl and di(C₁₋₆)alkylamino(C₁₋₆)alkylcarbonyl.

Selected examples of suitable substituents on the monocyclic ring ofwhich M is the residue include oxo, C₂₋₆ alkylcarbonyl,hydroxy(C₁₋₆)alkylcarbonyl, di(C₁₋₆)alkyl-amino(C₁₋₆)alkylcarbonyl,carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl,hydroxy-(C₁₋₆)alkylcarbonylamino, (C₃₋₇)cycloalkylcarbonylamino,aminocarbonyl and C₁₋₆ alkylaminocarbonyl.

Illustrative examples of suitable substituents on the monocyclic ring ofwhich M is the residue include oxo and C₂₋₆ alkylcarbonyl.

Typical examples of specific substituents on the monocyclic ring ofwhich M is the residue include fluoro, chloro, bromo, methyl, ethyl,isopropyl, pyridinyl, pyrazinyl, methoxy, isopropoxy, difluoromethoxy,trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulphonyl,hydroxy, hydroxymethyl, hydroxyethyl, cyano, trifluoromethyl, oxo,acetyl, ethylcarbonyl, tert-butylcarbonyl, cyclopropylcarbonyl,morpholinylcarbonylmethyl, carboxy, carboxymethyl, methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl,ethoxycarbonylmethyl, amino, aminomethyl, methylamino, ethylamino,dimethylamino, phenylamino, pyridinylamino, acetylamino,hydroxyacetylamino, cyclopropylcarbonylamino, tert-butoxycarbonylamino,methylsulphonylamino, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl and dimethylaminocarbonylmethyl. Additionalexamples include hydroxyacetyl and dimethylaminoacetyl.

Selected examples of specific substituents on the monocyclic ring ofwhich M is the residue include oxo, acetyl, hydroxyacetyl,dimethylaminoacetyl, carboxy, carboxymethyl, methoxycarbonyl,hydroxyacetylamino, cyclopropylcarbonylamino, aminocarbonyl andmethylaminocarbonyl.

Illustrative examples of specific substituents on the monocyclic ring ofwhich M is the residue include oxo and acetyl.

A particular substituent on the monocyclic ring of which M is theresidue is oxo.

Typical values of the monocyclic ring of which M is the residue includepyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,3-(acetylamino)pyrrolidin-1-yl, 3-(hydroxy-acetylamino)pyrrolidin-1-yl,3-(cyclopropylcarbonylamino)pyrrolidin-1-yl, imidazolidin-1-yl,4-(acetylamino)piperidin-1-yl, 4-(methylsulphonylamino)piperidin-1-yl,morpholin-4-yl, 3-methylmorpholin-4-yl, thiomorpholin-4-yl,1,1-dioxothiomorpholin-4-yl, piperazin-1-yl,4-(pyridin-2-yl)piperazin-1-yl, 4-(pyrazin-2-yl)piperazin-1-yl,4-(methylsulphonyl)piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,3-oxopiperazin-1-yl, 4-methyl-3-oxopiperazin-1-yl,4-acetylpiperazin-1-yl, 4-(ethylcarbonyl)piperazin-1-yl,4-(tert-butylcarbonyl)piperazin-1-yl,4-(cyclopropylcarbonyl)piperazin-1-yl,4-(morpholin-4-ylcarbonylmethyl)piperazin-1-yl,4-(carboxymethyl)piperazin-1-yl, 4-(methoxy-carbonyl)piperazin-1-yl,4-(ethoxycarbonylmethyl)piperazin-1-yl,4-(dimethylamino-carbonylmethyl)piperazin-1-yl and5-oxo-[1,4]diazepan-1-yl. Additional values include4-carboxypiperidin-1-yl, 4-(aminocarbonyl)piperidin-1-yl,4-(hydroxyacetyl)piperazin-1-yl, 4-(dimethylaminoacetyl)piperazin-1-yland 4-(methylaminocarbonyl)piperazin-1-yl.

Selected values of the monocyclic ring of which M is the residue include3-(hydroxyacetylamino)pyrrolidin-1-yl,3-(cyclopropylcarbonylamino)pyrrolidin-1-yl, 4-carboxypiperidin-1-yl,4-(aminocarbonyl)piperidin-1-yl, 3-oxopiperazin-1-yl,4-acetyl-piperazin-1-yl, 4-(hydroxyacetyl)piperazin-1-yl,4-(dimethylaminoacetyl)piperazin-1-yl, 4-(carboxymethyl)piperazin-1-yl,4-(methoxycarbonyl)piperazin-1-yl and 4-(methyl-aminocarbonyl)piperazin-1-yl.

Particular values of the monocyclic ring of which M is the residueinclude 3-oxopiperazin-1-yl and 4-acetylpiperazin-1-yl.

A favoured value of the monocyclic ring of which M is the residue is3-oxo-piperazin-1-yl.

Typical values of R¹, R² and/or R³ include hydrogen, halogen, C₁₋₆alkyl, aryl(C₁₋₆)alkyl and C₁₋₆ alkoxy.

Suitably, R¹, R² and R³ independently represent hydrogen, fluoro,chloro, bromo, cyano, nitro, methyl, ethyl, trifluoromethyl, benzyl,hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio,methylsulfinyl, methylsulfonyl, amino, methylamino, dimethylamino,acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl,carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl ordimethylaminosulfonyl.

Typically, R¹ represents hydrogen, halogen, C₁₋₆ alkyl, aryl(C₁₋₆)alkylor C₁₋₆ alkoxy.

Illustrative values of R¹ include hydrogen, halogen and C₁₋₆ alkyl.

In one embodiment, R¹ represents hydrogen. In another embodiment, R¹represents halogen, particularly fluoro or chloro. In one aspect of thatembodiment, R¹ represents fluoro. In another aspect of that embodiment,R¹ represents chloro. In a further embodiment, R¹ represents C₁₋₆ alkyl,particularly methyl or ethyl. In one aspect of that embodiment, R¹represents methyl. In another aspect of that embodiment, R¹ representsethyl. In a still further embodiment, R¹ represents aryl(C₁₋₆)alkyl,especially benzyl. In an additional embodiment, R¹ represents C₁₋₆alkoxy, especially methoxy.

Typically, R² represents hydrogen or halogen.

In one embodiment, R² represents hydrogen. In another embodiment, R²represents halogen, particularly fluoro or chloro. In one aspect of thatembodiment, R² represents fluoro. In another aspect of that embodiment,R² represents chloro.

Typically, R³ represents hydrogen.

In a particular embodiment, R² and R³ both represent hydrogen.

Typical examples of suitable substituents on R⁴ and/or R⁵ and/or R⁶and/or R⁷ include halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, difluoromethoxy,trifluoromethoxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆alkylsulphonyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, cyano,trifluoromethyl, oxo, C₂₋₆ alkylcarbonyl, carboxy, C₂₋₆ alkoxycarbonyl,amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, phenylamino, pyridinylamino,C₂₋₆ alkylcarbonylamino, C₂₋₆ alkoxycarbonylamino and aminocarbonyl.

Typical examples of specific substituents on R⁴ and/or R⁵ and/or R⁶and/or R⁷ include fluoro, chloro, bromo, methyl, ethyl, isopropyl,methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl,methylthio, ethylthio, methylsulphonyl, hydroxy, hydroxymethyl,hydroxyethyl, aminomethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, amino,methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino,acetylamino, tert-butoxycarbonylamino and aminocarbonyl.

Typical values of R⁴ include hydrogen, C₁₋₆ alkyl, —SR^(a), —SO₂R^(a)and —NR^(b)R^(c).

Suitable values of R⁴ include hydrogen, —SR^(a) and —SO₂R^(a).

In one embodiment, R⁴ represents hydrogen. In another embodiment, R⁴represents C₁₋₆ alkyl, especially methyl. In a further embodiment, R⁴represents —SR^(a). In a further embodiment, R⁴ represents —SO₂R^(a). Inan additional embodiment, R⁴ represents —NR^(b)R^(c).

Suitable values of R⁵ include hydrogen, C₁₋₆ alkyl and —NR^(b)R^(c).Typical values of R⁵ include hydrogen and C₁₋₆ alkyl.

In one embodiment, R⁵ represents hydrogen. In another embodiment, R⁵represents C₁₋₆ alkyl, especially methyl. In a further embodiment, R⁵represents —NR^(b)R^(c).

Suitable values of R⁶ include hydrogen, C₁₋₆ alkyl and —NR^(b)R^(c).Typical values of R⁶ include hydrogen and C₁₋₆ alkyl.

In one embodiment, R⁶ represents hydrogen. In another embodiment, R⁶represents C₁₋₆ alkyl, especially methyl. In a further embodiment, R⁶represents —NR^(b)R^(c).

Alternatively, R⁵ and R⁶, when taken together with the carbon atoms towhich they are attached, may form an optionally substituted C₅₋₇cycloalkenyl ring fused to the five-membered ring containing thevariable V. Thus, R⁵ and R⁶ may together represent a —(CH₂)₃—, —(CH₂)₄—or —(CH₂)₅— chain, wherein each of the carbon atoms in the respectivechain may be unsubstituted, or independently substituted by one or more,typically by one or two, substituents. Suitably, R⁵ and R⁶ togetherrepresent —CH₂CH₂CH₂—.

Suitable values of R⁷ include hydrogen, C₁₋₆ alkyl and —NR^(b)R^(c).

In one embodiment, R⁷ represents hydrogen. In another embodiment, R⁷represents C₁₋₆ alkyl, especially methyl. In a further embodiment, R⁷represents —NR^(b)R^(c).

In one embodiment, R⁸ represents hydrogen. In another embodiment, R⁸represents C₁₋₆ alkyl, especially methyl.

Suitable values of the group R⁸ include hydrogen and methyl.

Typically, R⁹ represents hydrogen or C₁₋₆ alkyl.

In one embodiment, R⁹ represents hydrogen. In another embodiment, R⁹represents halogen, particularly fluoro or chloro. In one aspect of thatembodiment, R⁹ represents fluoro. In another aspect of that embodiment,R⁹ represents chloro. In a further embodiment, R⁹ represents C₁₋₆ alkyl,especially methyl. In an additional embodiment, R⁹ represents C₁₋₆alkoxy, especially methoxy.

Suitable values of the group R⁹ include hydrogen, fluoro, chloro, bromo,methyl and methoxy. Suitably, R⁹ represents hydrogen or methyl.Typically, R⁹ represents hydrogen.

In one embodiment, R^(a) represents C₁₋₆ alkyl, especially methyl. Inanother embodiment, R^(a) represents difluoromethyl. In a furtherembodiment, R^(a) represents trifluoromethyl.

Suitably, R^(b) represents hydrogen; or C₁₋₆ alkyl or aryl(C₁₋₆)alkyl,either of which groups may be optionally substituted by one or moresubstituents.

Typical values of R^(b) include hydrogen and C₁₋₆ alkyl.

Illustratively, R^(b) represents hydrogen or trifluoromethyl; or methyl,ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, pentyl,hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl,tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperidinyl,homopiperidinyl, morpholinyl, azetidinylmethyl, tetrahydrofurylmethyl,pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl,thiazolidinylmethyl, imidazolidinylethyl, piperidinylmethyl,piperidinylethyl, tetrahydroquinolinylmethyl, piperazinylpropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl, pyridinyl,indolylmethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl,imidazolylethyl, benzimidazolylmethyl, triazolylmethyl, pyridinylmethylor pyridinylethyl, any of which groups may be optionally substituted byone or more substituents.

Typical examples of suitable substituents on R^(b) include halogen, C₁₋₆alkyl, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, cyano, trifluoromethyl, oxo, C₂₋₆alkylcarbonyl, carboxy, C₂₋₆ alkoxycarbonyl, amino, C₁₋₆ alkylamino,di(C₁₋₆)-alkylamino, phenylamino, pyridinylamino, C₂₋₆alkylcarbonylamino, C₂₋₆ alkoxycarbonyl-amino and aminocarbonyl.

Typical examples of specific substituents on R^(b) include fluoro,chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy,difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio,methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl,cyano, trifluoromethyl, oxo, acetyl, carboxy, methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl, amino, methylamino, ethylamino,dimethylamino, phenylamino, pyridinylamino, acetylamino,tert-butoxycarbonylamino and aminocarbonyl.

In one embodiment, R^(b) represents hydrogen. In another embodiment,R^(b) represents C₁₋₆ alkyl, especially methyl. In a further embodiment,R^(b) represents optionally substituted aryl(C₁₋₆)alkyl. In one aspectof that embodiment, R^(b) represents methoxy-benzyl.

Suitably, R^(c) represents hydrogen or C₁₋₆ alkyl. In one embodiment,R^(c) is hydrogen. In another embodiment, R^(c) represents C₁₋₆ alkyl,especially methyl or ethyl, particularly methyl. In a furtherembodiment, R^(c) represents C₃₋₇ cycloalkyl, e.g. cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl.

In one embodiment, R^(d) represents hydrogen. In another embodiment,R^(d) represents C₁₋₆ alkyl, especially methyl.

Suitably, R^(e) represents methyl.

One sub-class of compounds according to the invention is represented bythe compounds of formula (IIA) and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof:

wherein E, Q, M, R¹, R², R⁵ and R⁶ are as defined above.

Another sub-class of compounds according to the invention is representedby the compounds of formula (IIB) and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof:

wherein E, Q, M, R¹, R², R⁵ and R⁶ are as defined above.

Specific novel compounds in accordance with the present inventioninclude each of the compounds whose preparation is described in theaccompanying Examples, and pharmaceutically acceptable salts andsolvates thereof.

The present invention also provides a pharmaceutical composition whichcomprises a compound in accordance with the invention as describedabove, or a pharmaceutically acceptable salt or solvate thereof, inassociation with one or more pharmaceutically acceptable carriers.

Pharmaceutical compositions according to the invention may take a formsuitable for oral, buccal, parenteral, nasal, topical, ophthalmic orrectal administration, or a form suitable for administration byinhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methyl cellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogenphosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles or preservatives. Thepreparations may also contain buffer salts, flavouring agents, colouringagents or sweetening agents, as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formula (IA) and (IB) may be formulated for parenteraladministration by injection, e.g. by bolus injection or infusion.Formulations for injection may be presented in unit dosage form, e.g. inglass ampoules or multi-dose containers, e.g. glass vials. Thecompositions for injection may take such forms as suspensions, solutionsor emulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising, preserving and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds offormula (IA) and (IB) may also be formulated as a depot preparation.Such long-acting formulations may be administered by implantation or byintramuscular injection.

For nasal administration or administration by inhalation, the compoundsaccording to the present invention may be conveniently delivered in theform of an aerosol spray presentation for pressurised packs or anebuliser, with the use of a suitable propellant, e.g.dichlorodifluoromethane, fluorotrichloromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack or dispensing device may be accompanied byinstructions for administration.

For topical administration the compounds of use in the present inventionmay be conveniently formulated in a suitable ointment containing theactive component suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Particular carriers include, for example, mineraloil, liquid petroleum, propylene glycol, polyoxyethylene,polyoxypropylene, emulsifying wax and water. Alternatively, thecompounds of use in the present invention may be formulated in asuitable lotion containing the active component suspended or dissolvedin one or more pharmaceutically acceptable carriers. Particular carriersinclude, for example, mineral oil, sorbitan monostearate, polysorbate60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanoland water.

For ophthalmic administration the compounds of use in the presentinvention may be conveniently formulated as micronized suspensions inisotonic, pH-adjusted sterile saline, either with or without apreservative such as a bactericidal or fungicidal agent, for examplephenylmercuric nitrate, benzylalkonium chloride or chlorhexidineacetate. Alternatively, for ophthalmic administration compounds may beformulated in an ointment such as petrolatum.

For rectal administration the compounds of use in the present inventionmay be conveniently formulated as suppositories. These can be preparedby mixing the active component with a suitable non-irritating excipientwhich is solid at room temperature but liquid at rectal temperature andso will melt in the rectum to release the active component. Suchmaterials include, for example, cocoa butter, beeswax and polyethyleneglycols.

The quantity of a compound of use in the invention required for theprophylaxis or treatment of a particular condition will vary dependingon the compound chosen and the condition of the patient to be treated.In general, however, daily dosages may range from around 10 ng/kg to1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01mg/kg to 40 mg/kg body weight, for oral or buccal administration, fromaround 10 ng/kg to 50 mg/kg body weight for parenteral administration,and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg toaround 1000 mg, for nasal administration or administration by inhalationor insufflation.

The compounds of formula (IA) and (IB) above wherein Q representsoxygen, sulphur or N—R⁸ may be prepared by a process which comprisesreacting a compound of formula (III) with a compound of formula (IVA) or(IVB) respectively:

wherein Q¹ represents oxygen, sulphur or N—R⁸, L¹ represents a suitableleaving group, and V, Y, X, E, M, W, R¹, R², R³, R⁴, R⁵ and R⁸ are asdefined above.

The leaving group L¹ is typically a halogen atom, e.g. bromo or iodo.

The reaction is conveniently effected at ambient or elevated temperaturein a suitable solvent, e.g. N,N-dimethylformamide or acetonitrile. Thereaction may be performed in the presence of a suitable base, e.g. aninorganic base such as potassium carbonate, cesium carbonate, sodiumhydride or aqueous sodium hydroxide.

The intermediates of formula (III) above wherein L¹ is bromo or iodo maybe prepared from a compound of formula (V):

wherein E, M, W, R¹, R² and R³ are as defined above; by bromination oriodination.

The bromination reaction is conveniently effected by stirring compound(V) with an appropriate brominating agent, e.g. phosphorus tribromide,in a suitable solvent, e.g. a halogenated hydrocarbon such asdichloromethane

The iodination reaction is conveniently effected by stirring compound(V) with an appropriate iodinating agent, e.g. elemental iodine, in asuitable solvent, e.g. a halogenated hydrocarbon such asdichloromethane, typically in the presence of triphenylphosphine andimidazole.

Alternatively, the intermediates of formula (III) above wherein Erepresents methylene and L¹ is bromo may be prepared from a compound offormula (VI):

wherein M, W, R¹, R² and R³ are as defined above; by bromination.

The reaction is conveniently effected at an elevated temperature in asuitable solvent, e.g. a halogenated solvent such as carbontetrachloride, in the presence of a suitable brominating agent, e.g.N-bromosuccinimide, typically in the presence of a catalyst such asbenzoyl peroxide.

In another procedure, the compounds of formula (IA) and (IB) wherein Qrepresents oxygen may be prepared by a process which comprises reactinga compound of formula (V) as defined above with a compound of formula(VIIA) or (VIIB) respectively:

wherein V, Y, X, R⁴ and R⁵ are as defined above, and L² represents asuitable leaving group.

The leaving group L² is typically a halogen atom, e.g. chloro or bromo.

The reaction is conveniently effected by stirring compound (V) andcompound (VIIA) or (VIIB) at an elevated temperature in a suitablesolvent, e.g. N,N-dimethyl-formamide or 1,4-dioxane, typically underbasic conditions, e.g. in the presence of an inorganic base such assodium hydride.

In another procedure, the compounds of formula (IA) and (IB) wherein Qrepresents sulfur may be prepared by a process which comprises reactinga compound of formula (VIIA) or (VIIB) as defined above respectivelywith a compound of formula (VIII):

wherein E, M, W, R¹, R² and R³ are as defined above.

The reaction is conveniently effected by stirring compound (VIIA) or(VIIB) and compound (VIII) in a suitable solvent, e.g. a lower alkanolsuch as methanol, typically under basic conditions, e.g. in the presenceof an alkali metal alkoxide such as sodium methoxide.

The intermediates of formula (VIII) may typically be prepared bytreating a suitable compound of formula (III) above with thiolaceticacid; followed by treatment of the resulting compound with a base, e.g.an alkali metal alkoxide such as sodium methoxide.

In another procedure, the compounds of formula (IA) and (IB) wherein Qrepresents N—R⁸ may be prepared by a process which comprises reacting acompound of formula (VIIA) or (VIIB) as defined above respectively witha compound of formula (IX):

wherein E, M, W, R¹, R², R³ and R⁸ are as defined above.

The reaction is conveniently effected at an elevated temperature in asuitable solvent, e.g. tetrahydrofuran, n-butanol,1-methyl-2-pyrrolidinone (NMP) or 1,4-dioxane. The reaction may beperformed in the presence of a suitable base, e.g. an organic base suchas N,N-diisopropylethylamine.

The intermediates of formula (IX) wherein R⁸ represents hydrogen may beprepared by treating a suitable compound of formula (III) above withpotassium phthalimide; followed by treatment of the resulting compoundwith hydrazine. Alternatively, they may be prepared by treating asuitable compound of formula (III) above with sodium azide; followed bytreatment of the resulting compound with triphenylphosphine

In an additional procedure, the compounds of formula (IA) and (IB)wherein E represents methylene and Q represents N—R⁸ may be prepared bya process which comprises reacting a compound of formula (IVA) or (IVB)respectively wherein Q¹ represents N—R⁸ with a compound of formula (X):

wherein M, W, R¹, R² and R³ are as defined above; under reducingconditions.

The reaction is conveniently effected by stirring the reactants at anelevated temperature in a suitable solvent, e.g. a cyclic ether such astetrahydrofuran, in the presence of a reducing agent. A suitablereducing agent comprises a mixture of di-n-butyltin dichloride andphenylsilane.

The intermediates of formula (IX) wherein E represents methylene and R⁸represents C₁₋₆ alkyl, e.g. methyl, may be prepared by treating asuitable compound of formula (X) above with a C₁₋₆ alkylamine, e.g.methylamine, in the presence of titanium(IV) n-propoxide and a base,e.g. an organic base such as N,N-diisopropylamine; followed by treatmentof the resulting compound with a reducing agent, e.g. sodiumtriacetoxyborohydride.

The intermediates of formula (V) wherein E represents methylene may beprepared from the corresponding compound of formula (X) by treatmentwith a reducing agent, e.g. sodium borohydride.

The intermediates of formula (V), (VIII) and (IX) may be prepared byreacting a compound of formula (XI) with a compound of formula (XII):

wherein E, Q¹, W, R¹, R² and R³ are as defined above, and L³ representsa suitable leaving group.

The leaving group L³ is typically a halogen atom, e.g. chloro.

The reaction is conveniently effected at an elevated temperature in asuitable solvent, e.g. tetrahydrofuran, n-butanol,1-methyl-2-pyrrolidinone (NMP) or ethylene glycol dimethyl ether (DME).The reaction may be performed in the presence of a suitable base, e.g.an organic base such as N,N-diisopropylethylamine.

The intermediates of formula (XI) wherein E represents (methyl)methyleneand Q¹ represents NH may be prepared by a three-step procedure whichcomprises: (i) treating a suitable compound of formula (XIII):

wherein W, R¹, R², R³ and L³ are as defined above; with2-methyl-2-propanesulfinamide in the presence of titanium(IV)isopropoxide; (ii) reaction of the resulting compound with a Grignardreagent, e.g. methylmagnesium bromide; and (iii) treatment of theresulting compound with a mineral acid, e.g. hydrochloric acid.

Similarly, the intermediates of formula (XI) wherein E representsmethylene and Q¹ represents NH may be prepared by a three-step procedurewhich comprises: (i) treating a suitable compound of formula (XIII)above with 2-methyl-2-propanesulfinamide in the presence of titanium(IV)isopropoxide; (ii) reaction of the resulting compound with a reducingreagent, e.g. sodium borohydride; and (iii) treatment of the resultingcompound with a mineral acid, e.g. hydrochloric acid.

Where they are not commercially available, the starting materials offormula (IVA), (IVB), (VI), (VIIA), (VIIB), (X), (XII) and (XIII) may beprepared by methods analogous to those described in the accompanyingExamples, or by standard methods well known from the art.

It will be understood that any compound of formula (IA) or (IB)initially obtained from any of the above processes may, whereappropriate, subsequently be elaborated into a further compound offormula (IA) or (IB) by techniques known from the art. By way ofexample, a compound of formula (IA) or (IB) which contains an estermoiety, e.g. methoxycarbonyl or ethoxycarbonyl, may be converted intothe corresponding compound of formula (IA) or (IB) containing a carboxy(—CO₂H) moiety under standard saponification conditions, typically bytreatment with an inorganic base, e.g. an alkali metal hydroxide such assodium hydroxide or lithium hydroxide.

Where a mixture of products is obtained from any of the processesdescribed above for the preparation of compounds according to theinvention, the desired product can be separated therefrom at anappropriate stage by conventional methods such as preparative HPLC; orcolumn chromatography utilising, for example, silica and/or alumina inconjunction with an appropriate solvent system.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques. In particular,where it is desired to obtain a particular enantiomer of a compound offormula (IA) or (IB) this may be produced from a corresponding mixtureof enantiomers using any suitable conventional procedure for resolvingenantiomers. Thus, for example, diastereomeric derivatives, e.g. salts,may be produced by reaction of a mixture of enantiomers of formula (IA)or (IB), e.g. a racemate, and an appropriate chiral compound, e.g. achiral base. The diastereomers may then be separated by any convenientmeans, for example by crystallisation, and the desired enantiomerrecovered, e.g. by treatment with an acid in the instance where thediastereomer is a salt. In another resolution process a racemate offormula (IA) or (IB) may be separated using chiral HPLC. Moreover, ifdesired, a particular enantiomer may be obtained by using an appropriatechiral intermediate in one of the processes described above.Alternatively, a particular enantiomer may be obtained by performing anenantiomer-specific enzymatic biotransformation, e.g. an esterhydrolysis using an esterase, and then purifying only theenantiomerically pure hydrolysed acid from the unreacted ester antipode.Chromatography, recrystallisation and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular geometric isomer of the invention.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 3^(rd) edition, 1999. The protecting groups may be removedat any convenient subsequent stage utilising methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds in accordance with this invention potently inhibit theactivity of human PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ.

Enzyme Inhibition Assays

Measurement of the ability of compounds to inhibit the lipid kinaseactivity of the four class 1 PI3 kinase isoforms (α, β, γ and δ) wasperformed using a commercially available homogeneous time-resolvedfluorescence assay as described by Gray et al., Anal. Biochem., 2003,313, 234-245, according to the manufacturer's instructions (Upstate).All assays were performed at 2 μM ATP and a concentration of purifiedclass 1 PI3 kinase known to generate product within the linear range ofthe assay. Dilutions of inhibitor in DMSO were added to the assay andcompared with assays run in the presence of 2% (v/v) DMSO alone (100%activity). The concentration of inhibitor required to inhibit the enzymeactivity by 50% is quoted as the IC₅₀.

When tested in the above assay, the compounds of the accompanyingExamples were all found to possess IC₅₀ values for inhibition ofactivity of human PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ of 50 μMor better.

EXAMPLES

Abbreviations DCM: dichloromethane Et₂O: diethyl ether DIPEA:N,N-diisopropylethylamine EtOAc: ethyl acetate MeOH: methanol EtOH:ethanol n-BuOH: n-butanol NMP : 1-methyl-2-pyrrolidinone THF:tetrahydrofuran TFA: trifluoroacetic acid Me: methyl MeCN: acetonitrileDMF: N,N-dimethylformamide DMSO: dimethylsulfoxide r.t.: roomtemperature RT: retention time SiO₂: silica h: hour br: broad M: massHPLC: High Performance Liquid Chromatography LCMS: Liquid ChromatographyMass Spectrometry ES+: Electrospray Positive Ionisation

Analytical Conditions

All NMRs were obtained at 400 MHz.

Compounds were named with the aid of the Cambridgesoft ChemistryCartridge (v. 9.0.0.182) software.

All reactions involving air- or moisture-sensitive reagents wereperformed under a nitrogen atmosphere using dried solvents andglassware.

Analytical Condition Method Description 10 cm_ESCI_AmmBicarb_MeCN 1Solvents: Acetonitrile (far UV grade) 10 cm_ESCI_Bicarb_MeCN Water (highpurity via PureLab 10 cm_ESI_Bicarb Option unit) with 10 mM ammoniumhydrogencarbonate 10 cm_ESI_Bicarb_MeCN Column: Waters Xterra MS 5 μmC18, 10 cm_APCI_Formic 100 × 4.6 mm (Plus guard cartridge) Flow Rate 2mL/min Gradient: A: Water/Bicarb B: MeCN Time A % B % 0.00 95 5 0.50 955 4.00 5 95 5.50 5 95 5.60 95 5 6.50 95 5 10 cm_ESI_Formic 2 Solvents:Acetonitrile (far UV grade) with 10 cm_ESI_Formic_MeCN 0.1% (v/v) formicacid Water (high purity via PureLab Option unit) with 0.1% formic acidColumn: Phenomenex Luna 5 μm C18 (2), 100 × 4.6 mm (Plus guardcartridge) Flow Rate: 2 mL/min Gradient: A: Water/formic acid B:MeCN/formic acid Time A % B % 0.00 95 5 3.50 5 95 5.50 5 95 5.60 95 56.50 95 5

Intermediate 1(R,E)-N-[(2,8-Dichloroquinolin-3-yl)methylidene]-2-methylpropane-2-sulfinamide

To a solution of 2,8-dichloroquinoline-3-carboxaldehyde (43.0 g, 0.19mol) in anhydrous THF (500 mL) was added titanium(IV) isopropoxide (114mL, 0.38 mol) at r.t. After stirring for 15 minutes,(R)-2-methyl-2-propanesulfinamide (23.0 g, 0.19 mol) was added andstirring was continued for 17 h at r.t. Water (1 L) was added to thereaction mixture and the resulting precipitate was filtered and washedwith DCM. The organic layer was dried (Na₂SO₄) and concentrated in vacuoto give the title compound (61 g, 97%) as a pale yellow solid. δ_(H)(CDCl₃) 9.11 (1H, s), 8.83 (1H, s), 7.93 (1H, dd, J 7.54, 1.31 Hz), 7.88(1H, dd, J 8.22, 1.31 Hz), 7.55 (1H, t, J 7.88 Hz), 1.33 (9H, s).

Intermediate 2(R)—N—[(S)-1-(2,8-Dichloroquinolin-3-yl)ethyl]-2-methylpropane-2-sulfinamide

To a solution of Intermediate 1 (61 g, 0.18 mol) in DCM (1.5 L) wasadded dropwise methylmagnesium bromide (123.5 mL, 0.37 mol; 3M in Et₂O)over 50 minutes at −70° C. under nitrogen. The reaction mixture wasallowed to reach r.t. with stirring overnight. The mixture was cooled inan ice-salt bath and saturated aqueous NH₄Cl (500 mL) was slowly added.The aqueous layer was extracted with DCM (2×500 mL). The combinedorganic layers were dried (MgSO₄) and concentrated in vacuo. The residuewas triturated with Et₂O and the solid filtered, washed with Et₂O anddried under reduced pressure to give the title compound (32 g, 50%) as apale pink solid. δ_(H) (CDCl₃) 8.26 (1H, s), 7.83 (1H, dd, J 7.52, 1.32Hz), 7.74 (1H, dd, J 8.19, 1.32 Hz), 7.49 (1H, t, J 7.86 Hz), 5.16-5.07(1H, m), 3.47 (1H, d, J 4.63 Hz), 1.71 (3H, d, J 6.75 Hz), 1.25 (9H, s).

Intermediate 3 (S)-1-(2,8-Dichloroquinolin-3-yl)ethanamine

To a solution of Intermediate 2 (37.7 g, 0.11 mol) in MeOH (370 mL) wasadded 4M hydrogen chloride in 1,4-dioxane (58 mL) at r.t. The reactionmixture was stirred for 2 h and concentrated in vacuo. The residue waspartitioned between 5M HCl (300 mL) and DCM (300 mL). The organic layerwas extracted with 5M aqueous HCl (100 mL) and the combined aqueouslayers basified with aqueous NaOH and extracted with DCM (3×500 mL) andchloroform (3×500 mL). The organic layers were dried (MgSO₄) andconcentrated in vacuo to afford the title compound (23.7 g, 90%) as anamber oil. δ_(H) (CDCl₃) 8.40 (1H, s), 7.80 (1H, dd, J 7.51, 1.33 Hz),7.75 (1H, dd, J 8.19, 1.33 Hz), 7.46 (1H, t, J 7.86 Hz), 4.67 (1H, q, J6.52 Hz), 1.50 (3H, d, J 6.53 Hz).

Intermediate 4 (S)-tert-Butyl1-(2,8-dichloroquinolin-3-yl)ethylcarbamate

To a stirred solution of Intermediate 3 (23.7 g, 98 mmol) and DIPEA (51mL, 0.3 mol) in DCM (1 L) was added di-tert-butyl dicarbonate (25.7 g,118 mmol). The reaction mixture was allowed to stand at r.t. overnightand concentrated in vacuo. The residue was triturated with 40-60petroleum ether, filtered, washed with 40-60 petroleum ether and driedunder reduced pressure to give the title compound (28.4 g, 85%) as acolourless solid. δ_(H) (CDCl₃) 8.13 (1H, s), 7.80 (1H, dd, J 7.51, 1.32Hz), 7.72 (1H, dd, J 8.18, 1.31 Hz), 7.46 (1H, t, J 7.85 Hz), 5.23-5.16(1H, m), 5.10 (1H, br s), 1.55 (3H, br d, J 7.18 Hz), 1.42 (9H, br s).

Intermediate 5 (S)-tert-Butyl1-[8-chloro-2-(3-oxopiperazin-1-yl)quinolin-3-yl]ethylcarbamate

A mixture of Intermediate 4 (0.53 g, 1.56 mmol), 2-oxopiperazine (0.78g, 7.78 mmol) and DIPEA (1.35 mL, 7.78 mmol) in NMP (10 mL) was heatedat 140° C. for 16 h. After cooling, Et₂O (250 mL) was added and themixture washed with water (3×100 mL) and brine (100 mL). The organiclayer was separated, dried (MgSO₄), concentrated in vacuo and theresidue purified by column chromatography on silica, eluting with 0-100%EtOAc in isohexane, to afford the title compound (0.34 g, 53%) as a paleyellow solid. δ_(H) (CDCl₃) 8.03 (1H, s), 7.72 (1H, dd, J 7.5, 1.3 Hz),7.63 (1H, dd, J 8.0, 1.3 Hz), 7.32 (1H, t, J 7.8 Hz), 6.32 (1H, br s),5.15-4.93 (2H, m), 4.36 (1H, d, J 17.7 Hz), 4.13-3.84 (2H, m), 3.77-3.68(1H, m), 3.45 (2H, m), 1.48-1.42 (12H, m).

Intermediate 6(S)-4-[3-(1-Aminoethyl)-8-chloroquinolin-2-yl]piperazin-2-one

TFA (1 mL) was added to a stirred solution of Intermediate 5 (0.34 g,0.83 mmol) in DCM (5 mL) and the mixture was allowed to stand at r.t.for 16 h before being concentrated in vacuo. The residue was dissolvedin DCM (20 mL) and washed with 0.1M NaOH solution. 15% aqueous NaOHsolution was added to the aqueous layer which was extracted with EtOAc(20 mL) and DCM (2×20 mL). The combined organics were dried (MgSO₄) andconcentrated in vacuo to afford the title compound (0.24 g, 95%) as apale orange-yellow solid. δ_(H) (CDCl₃) 8.41 (1H, s), 7.73-7.66 (2H, m),7.38-7.27 (1H, m), 4.81 (1H, m), 4.02 (1H, d, J 17.5 Hz), 3.88 (1H, d, J17.5 Hz), 3.59-3.38 (4H, m), 2.93 (3H, br s), 1.69 (3H, d, J 6.7 Hz).

Intermediate 7(E)-N-[2-Chloro-7-fluoro-8-methylquinolin-3-yl)methylidene]-(R)-2-methylpropane-2-sulfinamide

Following the procedure described for Intermediate1,2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde (6.6 g, 29.5 mmol),titanium(IV) isopropoxide (17.0 g, 60 mmol),(R)-2-methyl-2-propanesulfinamide (3.6 g, 29.5 mmol) and THF (200 mL)gave the title compound (8.3 g, 86%) as a yellow solid. δ_(H) (CDCl₃)9.12 (1H, s), 8.73 (1H, s), 7.71 (1H, dd, J 6.0 Hz), 7.40 (1H, t, J 8.2Hz), 2.69 (3H, s), 1.32 (9H, s).

Intermediate 8N—[(S)-1-(2-Chloro-7-fluoro-8-methylquinolin-3-yl)ethyl]-(R)-2-methylpropane-2-sulfinamide

Following the procedure described for Intermediate 2, Intermediate 7(8.3 g, 25.4 mmol), methylmagnesium bromide (16.0 mL, 48 mmol; 3.0M inEt₂O), and DCM (100 mL) gave the title compound (4.2 g, 48%) as a yellowsolid. δ_(H) (CDCl₃) 8.17 (1H, s), 7.63 (1H, dd, J 6.0 Hz), 7.32 (1H, t,J 8.8 Hz), 5.16 (1H, q, J 6.8 Hz), 3.45 (1H, d, J 6.8 Hz), 2.66 (3H, s)1.70 (3H, d, J 6.8 Hz), 1.26 (9H, s).

Intermediate 9

(S)-tert-Butyl 1-(2-chloro-7-fluoro-8-methylquinolin-3-yl)ethylcarbamate

Following the procedure described for Intermediate 3 followed byIntermediate 4, Intermediate 8 (4.2 g, 12.2 mmol), conc. HCl (1 mL),di-tert-butyl dicarbonate (2.7 g, 12.2 mmol) and DIPEA (1.6 g, 12.2mmol) gave the title compound (4.38 g, 90%) as a yellow solid. δ_(H)(CDCl₃) 8.07 (1H, s), 7.62 (1H, dd, J 6.0 Hz), 7.30 (1H, t, J 8.8 Hz),5.17 (1H, m), 5.07 (1H, br s), 2.65 (3H, s) 1.54 (3H, d, J 6.4 Hz), 1.42(9H, s).

Intermediate 10 (S)-tert-Butyl1-[2-(4-acetylpiperazin-1-yl)-7-fluoro-8-methylquinolin-3-yl)]ethylcarbamate

Intermediate 9 (3.0 g, 0.89 mmol) in NMP (15 mL) was treated with1-acetyl-piperazine (2.8 g, 22 mmol) and DIPEA (5.7 g, 44 mmol) andheated in a sealed tube at 140° C. for 72 h. The reaction mixture wascooled to r.t. and diluted with ethyl acetate/water. The organic phasewas washed (water, brine), dried (phase separation cartridge) andevaporated in vacuo. The resulting residue was purified by silica flashchromatography, eluting with 50-60% EtOAc in isohexane, to give thetitle compound (3.4 g 89%) as a cream solid. δ_(H) (CDCl₃) 7.95 (1H, s),7.53 (1H, dd, J 8.9, 6.0 Hz), 7.16 (1H, t, J 8.9 Hz), 5.08-5.02 (1H, m),3.95-3.90 (1H, m), 3.78-3.73 (2H, m), 3.64 (1H, m), 3.61-3.40 (2H, m),3.19-3.15 (2H, m), 2.59 (3H, d, J 2.4 Hz), 2.17 (3H, s), 1.58 (3H, d, J6.5 Hz), 1.48-1.42 (9H, m).

Intermediate 11(S)-1-{4-[3-(1-Aminoethyl)-7-fluoro-8-methylquinolin-2-yl]piperazin-1-yl}ethanone

Intermediate 10 (3.4 g, 7.9 mmol) in DCM (20 mL) was treated with TFA(10 mL) and stirred for 30 minutes. The reaction mixture was evaporatedin vacuo. The residue was dissolved in MeOH and passed through an SCXcartridge, washing with MeOH and eluting with 7M NH₃/MeOH solution.After evaporation in vacuo, the title compound (2.6 g, 100%) wasobtained as a white foam. δ_(H) (CDCl₃) 8.12 (1H, s), 7.54 (1H, dd, J8.9, 6.1 Hz), 7.16 (1H, t, J 8.9 Hz), 4.53 (1H, q, J 6.5 Hz), 3.82 (2H,t, J 5.0 Hz), 3.72-3.64 (2H, m), 3.41-3.20 (4H, m), 2.59 (3H, d, J 2.4Hz), 2.17 (3H, s), 2.07 (2H, br s), 1.51 (3H, d, J 6.5 Hz).

Intermediate 12 (S)-tert-Butyl1-[7-fluoro-8-methyl-2-(3-oxopiperazin-1-yl)quinolin-3-yl]ethylcarbamate

Following the procedure described for Intermediate 5, Intermediate 9(280 mg, 0.83 mmol), 2-oxopiperazine (86 mg, 1.0 mmol) and DIPEA (0.5mL, 3.8 mmol) in n-BuOH (2.0 mL) gave the title compound (270 mg, 81%)as a purple oil. δ_(H) (CDCl₃) 7.99 (1H, s), 7.54 (1H, dd, J 8.9, 6.0Hz), 7.17 (1H, t, J 9.0 Hz), 6.73 (1H, br s), 5.10 (2H, br s), 4.28 (1H,d, J 17.5 Hz), 3.95 (1H, d, J 17.5 Hz), 3.89-3.77 (1H, m), 3.70-3.51(1H, m), 3.44-3.35 (2H, m), 2.58 (3H, d, J 2.4 Hz), 1.50-1.30 (12H, m).

Example 1(S)-4-{8-Chloro-3-[1-(7-methylthieno[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one

A solution of Intermediate 6 (100 mg, 0.33 mmol),4-chloro-7-methylthieno[3,2-d]pyrimidine (73 mg, 0.40 mmol) and DIPEA(0.29 mL, 1.65 mmol) in NMP (1.5 mL) was heated at 140° C. for 1 h undermicrowave irradiation. The crude mixture was purified by preparativeHPLC to yield title compound (10.2 mg, 7%) as a white solid. δ_(H)(DMSO-d₆) 8.46 (1H, s), 8.41-8.36 (2H, m), 7.99 (1H, s), 7.85-7.81 (3H,m), 7.41 (1H, t, J 7.8 Hz), 5.73 (1H, t, J 6.7 Hz), 4.21 (1H, d, J 17.2Hz), 4.13 (1H, d, J 13.2 Hz), 3.94 (1H, d, J 17.2 Hz), 3.64 (1H, d, J10.3 Hz), 3.47-3.37 (1H, m), 3.27-3.17 (1H, m), 2.37 (3H, d, J 1.2 Hz),1.57 (3H, d, J 6.7 Hz). LCMS (ES+) 453 (M+H)⁺, RT 2.31 minutes (Method2).

Example 2(S)-4-{8-Chloro-3-[1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one

A solution of Intermediate 6 (80 mg, 0.26 mmol),4-chlorothieno[2,3-d]-pyrimidine (67 mg, 0.39 mmol) and DIPEA (0.23 mL,1.3 mmol) in NMP (1.5 mL) was heated at 140° C. for 1 h under microwaveirradiation. The crude mixture was purified by preparative HPLC to yieldthe title compound (22.9 mg, 20%) as a white solid. δ_(H) (DMSO-d₆) 8.45(1H, d, J 6.7 Hz), 8.38 (1H, s), 8.34 (1H, s), 7.99 (1H, s), 7.88 (1H,d, J 6.1 Hz), 7.87-7.81 (2H, m), 7.67 (1H, d, J 6.0 Hz), 7.41 (1H, t, J7.8 Hz), 5.74-5.66 (1H, m), 4.22 (1H, d, J 17.2 Hz), 4.18-4.11 (1H, m),3.94 (1H, d, J 17.2 Hz), 3.63 (1H, m), 3.43 (1H, m), 3.40-3.26 (2H, m),1.58 (3H, d, J 6.6 Hz). LCMS (ES+) 439 (M+H)⁺, RT 2.97 minutes (Method2).

Example 3(S)-4-{8-Chloro-3-[1-(6-methylthieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one

A solution of Intermediate 6 (100 mg, 0.33 mmol),4-chloro-6-methylthieno[2,3-d]pyrimidine (73 mg, 0.40 mmol) and DIPEA(0.29 mL, 1.65 mmol) in NMP (1.5 mL) was heated at 150° C. for 1 h undermicrowave irradiation. The crude mixture was purified by preparativeHPLC to yield the title compound (27 mg, 18%) as an off-white solid.δ_(H) (DMSO-d₆) 8.37 (1H, s), 8.28-8.24 (2H, m), 7.99 (1H, s), 7.87-7.81(2H, m), 7.55 (1H, d, J 1.5 Hz), 7.42 (1H, t, J 7.8 Hz), 5.71-5.63 (1H,m), 4.21 (1H, d, J 17.2 Hz), 4.14 (1H, d, J 13.3 Hz), 3.94 (1H, d, J17.2 Hz), 3.63 (1H, d, J 10.0 Hz), 3.42 (1H, t, J 10.9 Hz), 3.33-3.26(1H, m), 2.60 (3H, d, J 1.3 Hz), 1.56 (3H, d, J 6.6 Hz). LCMS (ES+) 453(M+H)⁺, RT 3.13 minutes (Method 2).

Example 4(S)-1-(4-{3-[1-(2,3-Dihydro-1H-8-thia-5,7-diazacyclopenta[a]inden-4-ylamino)ethyl]-7-fluoro-8-methylquinolin-2-yl}piperazin-1-yl)ethanone

Intermediate 11 (75 mg, 0.20 mmol),4-chloro-2,3-dihydro-1H-8-thia-5,7-diaza-cyclopenta[a]indene (63 mg,0.30 mmol) and DIPEA (0.14 mL, 0.80 mmol) in NMP (1.2 mL) were heatedunder microwave conditions at 150° C. for 1 h. Purification bypreparative HPLC afforded the title compound (65 mg, 61%) as a whitesolid. δ_(H) (DMSO-d₆) 8.43 (1H, s), 8.29 (1H, s), 7.76 (1H, t, J 7.5Hz), 7.32 (1H, t, J 9.1 Hz), 6.69 (1H, d, J 7.2 Hz), 5.78-5.72 (1H, m),3.81-3.58 (6H, m), 3.35-3.13 (4FI, m), 3.11 (1H, d, J 12.0 Hz), 3.01(2H, t, J 7.19 Hz), 2.57 (3H, s), 2.10 (3H, s), 1.61 (3H, d, J 6.6 Hz),1H under DMSO. LCMS (ES+) 505 (M+H)⁺, RT 4.10 minutes (Method I).

Example 5N-[(3R)-1-{8-Chloro-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}pyrrolidin-3-yl]-2-hydroxyacetamide

(R)-(+)-3-Amino-1-(tert-Butoxycarbonyl)pyrrolidine (400 mg, 2.15 mmol),DCM (30 mL), DIPEA (2 mL), and acetoxyacetyl chloride (0.247 mL, 2.3mmol) were combined at r.t. under a nitrogen atmosphere. The reactionmixture was stirred for 7 days, then diluted with DCM (50 mL) and washedwith water (30 mL). The organic layer was separated, dried (MgSO₄) andconcentrated in vacuo to give a tan oil. This material, MeOH (10 mL) and2N HCl in Et₂O (4 mL) were stirred at r.t. for 1 day. The reactionmixture was concentrated in vacuo. The resulting crude material,Intermediate 4 (400 mg, 1.17 mmol), n-BuOH (14 mL) and DIPEA (2 mL) werecombined in a sealed tube and heated to 130° C. for 13 days. Thereaction mixture was cooled, concentrated onto silica and purified bycolumn chromatography (SiO₂, 0-100% EtOAc in isohexane then 10% MeOH inEtOAc) to give an off-white foam. This material, MeOH (10 mL) and 2N HClin Et₂O (6 mL) were combined and stirred at r.t. for 24 h. The reactionmixture was concentrated to give a yellow solid. A portion of thismaterial (50 mg, 0.13 mmol), n-BuOH (6 mL), DIPEA (1 mL) and4-chlorothieno[2,3-d]pyrimidine (50 mg, 0.25 mmol) were combined in asealed tube and heated under microwave irradiation to 160° C. for 2 h.The reaction mixture was concentrated to dryness and the residuepurified by preparative HPLC to give the title compound (10.6 mg, 17%)as an off-white solid. δ_(H) (DMSO-d₆) 8.41-8.33 (2H, m), 8.19 (1H, s),7.96 (1H, d, J 6.79 Hz), 7.88 (1H, d, J 5.99 Hz), 7.73-7.62 (3H, m),7.19 (1H, t, J 7.76 Hz), 5.64-5.54 (1H, m), 5.40 (1H, t, J 5.89 Hz),4.48 (1H, br s), 4.11-4.00 (2H, m), 3.88-3.76 (4H, m), 2.28-2.16 (1H,m), 2.16-2.05 (1H, m), 1.59 (3H, d, J 6.66 Hz). LCMS (ES+) 485/483(M+H)⁺, RT 2.52 minutes (Method 1).

Example 6(4-{7-Fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)aceticacid

Intermediate 9 (700 mg, 2.06 mmol), ethyl 2-(piperazin-1-yl)acetate (0.5g), n-BuOH (10 mL) and DIPEA (2 mL) were combined in a sealed tube andheated to 130° C. for 12 days. The reaction mixture was cooled,concentrated onto silica and purified by column chromatography (SiO₂,0-100% EtOAc in isohexane). The resulting material, EtOH (7 mL) and 2MHCl in Et₂O (5 mL) were combined and stirred at r.t. for 3 days. Themixture was concentrated to give a pale yellow solid. A portion of thismaterial (50 mg), n-BuOH (6 mL), DIPEA (1 mL) and4-chlorothieno[2,3-d]pyrimidine (50 mg, 0.25 mmol) were combined in asealed tube and heated under microwave irradiation to 160° C. for 2 h.15% NaOH solution (0.2 mL) was then added to the reaction mixture, whichwas stirred at r.t. for 3 days, concentrated to dryness and purified bypreparative HPLC to give the title compound (19.3 mg, 16%) as a whitesolid. δ_(H) (DMSO-d₆) 8.39-8.28 (3H, m), 7.87 (1H, d, J 6.00 Hz), 7.77(1H, dd, J 8.92, 6.29 Hz), 7.65 (1H, d, J 5.97 Hz), 7.30 (1H, t, J 9.11Hz), 5.80-5.71 (1H, m), 3.78-3.70 (2H, m), 3.27 (2H, s), 3.27-3.16 (2H,m), 2.96-2.88 (2H, m), 2.84-2.75 (2H, m), 2.58 (3H, s), 1.58 (3H, d, J6.65 Hz). LCMS (ES+) 481 (M+H)⁺, RT 2.51 minutes (Method 1).

Example 71-(4-{8-Chloro-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)-2-hydroxyethanone

Intermediate 4 (700 mg, 2.05 mmol), 2-hydroxy-1-(piperazin-1-yl)ethanonehydrochloride, n-BuOH (10 mL) and DIPEA (4 mL) were combined in a sealedtube and heated to 130° C. for 7 days. The mixture was cooled,concentrated onto silica and purified by column chromatography (SiO₂,0-10% MeOH in EtOAc) to give a yellow gum. This material, MeOH (5 mL)and 2M HCl in Et₂O (5 mL) were combined and stirred at r.t. for 24 h.The mixture was concentrated to give a yellow glass. A portion of thismaterial (50 mg, 0.13 mmol), n-BuOH (6 mL), DIPEA (1 mL) and4-chlorothieno[2,3-d]pyrimidine (50 mg, 0.25 mmol) were combined in asealed tube and heated under microwave irradiation to 160° C. for 2 h.The reaction mixture was concentrated to dryness and purified bypreparative HPLC to give the title compound (5.2 mg, 8%) as a brownglass. δ_(H) (DMSO-d₆) 8.40-8.33 (3H, m), 7.85-7.76 (3H, m), 7.63 (1H,d, J 5.98 Hz), 7.39 (1H, t, J 7.82 Hz), 5.81-5.71 (1H, m), 4.59 (1H, t,J 5.50 Hz), 4.19-4.13 (2H, m), 3.83-3.12 (8H, m), 1.57 (3H, d, J 6.69Hz). LCMS (ES+) 485/483 (M+H)⁺, RT 3.16 minutes (Method 1).

Example 81-(4-{8-Chloro-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)-2-(dimethylamino)ethanone

Intermediate 4 (700 mg, 2.05 mmol),2-(dimethylamino)-1-(piperazin-1-yl)-ethanone (500 mg), n-BuOH (10 mL)and DIPEA (4 mL) were combined in a sealed tube and heated to 130° C.for 10 days. The reaction mixture was cooled, concentrated onto silicaand purified by column chromatography (SiO₂, 0-10% MeOH in EtOAc) togive a cream solid. This material, MeOH (6 mL) and 2M HCl in Et₂O (6 mL)were combined and stirred at r.t. for 24 h. The mixture was concentratedto give a yellow foam. A portion of this material (50 mg, 0.12 mmol),n-BuOH (6 mL), DIPEA (1 mL) and 4-chlorothieno[2,3-d]pyrimidine (50 mg,0.25 mmol) were combined in a sealed tube and heated under microwaveirradiation to 160° C. for 2 h. The reaction mixture was concentrated todryness and purified by preparative HPLC to give the title compound (6.9mg, 11%) as a white solid. δ_(H) (DMSO-d₆) 8.44-8.36 (3H, m), 7.88-7.79(3H, m), 7.66 (1H, d, J 5.94 Hz), 7.42 (1H, t, J 7.80 Hz), 5.84-5.74(1H, m), 3.96-3.10 (10H, m), 2.24 (6H, s), 1.61 (3H, d, J 6.63 Hz). LCMS(ES+) 512/510 (M+H)⁺, RT 3.34 minutes (Method 1).

Example 91-{7-Fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperidine-4-carboxamide

Intermediate 9 (700 mg, 2.06 mmol), 4-piperidinecarboxamide (0.5 g),n-BuOH (10 mL) and DIPEA (4 mL) were combined in a sealed tube andheated to 130° C. for 12 days. The reaction mixture was cooled,concentrated onto silica and purified by column chromatography (SiO₂,0-10% MeOH in EtOAc) to give a clear gum. This material, MeOH (10 mL)and 2N HCl in Et₂O (7 mL) were combined and stirred at r.t. for 24 h.The reaction mixture was concentrated to give a yellow solid. A portionof this material (60 mg), n-BuOH (6 mL), DIPEA (1 mL) and4-chlorothieno[2,3-d]pyrimidine (50 mg, 0.25 mmol) were combined in asealed tube and heated under microwave irradiation to 160° C. for 2 h.The reaction mixture was concentrated to dryness and the residuepurified by preparative HPLC to give the title compound (18.3 mg) as abeige solid. δ_(H) (DMSO-d₆) 8.37-8.33 (2H, m), 8.27 (1H, s), 7.88 (1H,d, J 6.00 Hz), 7.74 (1H, dd, J 8.91, 6.34 Hz), 7.65 (1H, d, J 5.97 Hz),7.35-7.25 (2H, m), 6.82 (1H, s), 5.78-5.69 (1H, m), 4.19 (1H, d, J 12.65Hz), 3.67 (1H, d, J 12.62 Hz), 3.17 (1H, t, J 11.97 Hz), 2.70 (1H, t, J11.97 Hz), 2.57 (3H, s), 2.42-2.32 (1H, m), 1.99-1.90 (2H, m), 1.86-1.76(2H, m), 1.58 (3H, d, J 6.67 Hz). LCMS (ES+) 465 (M+H)⁺, RT 3.27 minutes(Method 1).

Example 101-{7-Fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperidine-4-carboxylicacid

Intermediate 9 (700 mg, 2.06 mmol), methyl 4-piperidinecarboxylatehydrochloride (500 mg, 2.78 mmol), n-BuOH (10 mL) and DIPEA (4 mL) werecombined in a sealed tube and heated to 130° C. for 12 days. Thereaction mixture was cooled, concentrated onto silica and purified bycolumn chromatography (SiO₂, 0-10% MeOH in EtOAc). The resultingmaterial, MeOH (10 mL) and 2N HCl in Et₂O (6 mL) were combined andstirred at r.t. for 24 h. The reaction mixture was concentrated to givea tan foam. A portion of this material (50 mg), n-BuOH (6 mL), DIPEA (1mL) and 4-chlorothieno[2,3-d]pyrimidine (50 mg, 0.25 mmol) were combinedin a sealed tube and heated under microwave irradiation to 160° C. for 2h. 15% NaOH solution (0.2 mL) was added to the reaction mixture whichwas stirred at r.t. for 3 days. The reaction mixture was concentrated todryness and purified by preparative HPLC to give the title compound(12.8 mg) as an off-white solid. δ_(H) (DMSO-d₆) 8.38-8.30 (2H, m), 8.27(1H, s), 7.87 (1H, d, J 6.00 Hz), 7.75 (1H, dd, J 8.90, 6.34 Hz), 7.64(1H, d, J 5.97 Hz), 7.28 (1H, t, J 9.12 Hz), 5.80-5.70 (1H, m), 4.09(1H, d, J 12.61 Hz), 3.60 (1H, d, J 12.86 Hz), 3.29-3.19 (1H, m),2.83-2.75 (1H, m), 2.56 (3H, s), 2.53-2.45 (1H, m), 2.13-2.02 (1H, m),1.94-1.85 (2H, m), 1.85-1.73 (1H, m), 1.58 (3H, d, J 6.68 Hz). LCMS(ES+) 466 (M+H)⁺, RT 2.36 minutes (Method 1).

Example 11N-[(3S)-1-{7-Fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-c]pyrimidin-4-ylamino)ethyl]-quinolin-2-yl}pyrrolidin-3-yl]cyclopropanecarboxamide

(S)-(−)-3-Amino-1-(tert-butoxycarbonyl)pyrrolidine (500 mg, 2.68 mmol),DCM (30 mL), DIPEA (2 mL) and cyclopropanecarbonyl chloride (0.275 mL, 3mmol) were combined at r.t. under a nitrogen atmosphere. The reactionmixture was stirred for 1 day, then diluted with DCM (50 mL) and washedwith water (50 mL). The organic layer was separated, dried (MgSO₄) andconcentrated in vacuo to give a brown oil. This oil, MeOH (10 mL) and 2NHCl in Et₂O (5 mL) were stirred at r.t. for 3 days. The reaction mixturewas concentrated in vacuo. The resulting crude material (2.68 mmol),Intermediate 9 (500 mg, 1.48 mmol), n-BuOH (16 mL) and DIPEA (2 mL) werecombined in a sealed tube and heated to 130° C. for 15 days. Thereaction mixture was cooled, concentrated onto silica and purified bycolumn chromatography (SiO₂, 0-100% EtOAc in isohexane) to give a tansolid. This solid, MeOH (10 mL) and 2M HCl in Et₂O (7 mL) were combinedand stirred at r.t. for 24 h. The reaction mixture was concentrated togive a brown glass. A portion of this material (50 mg, 0.127 mmol),n-BuOH (6 mL), DIPEA (1 mL) and 4-chlorothieno[2,3-d]pyrimidine (50 mg,0.25 mmol) were combined in a sealed tube and heated under microwaveirradiation to 160° C. for 2 h. The reaction mixture was concentrated todryness and purified by preparative HPLC to give the title compound(21.2 mg, 34%) as a tan solid. δ_(H) (DMSO-d₆) 8.43-8.34 (3H, m), 8.12(1H, s), 7.89 (1H, d, J 5.99 Hz), 7.67-7.59 (2H, m), 7.09 (1H, t, J 9.11Hz), 5.96-5.89 (1H, m), 4.43-4.38 (1H, m), 4.00-3.82 (3H, m), 3.69 (1H,dd, J 10.36, 7.52 Hz), 2.50 (3H, s), 2.29-2.23 (1H, m), 1.96-1.91 (1H,m), 1.63-1.53 (4H, m), 0.74-0.66 (4H, m). LCMS (ES+) 491 (M+H)⁺, RT 3.47minutes (Method 1).

Example 122-(Dimethylamino)-1-(4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)ethanone

Intermediate 9 (700 mg, 2.06 mmol),2-(dimethylamino)-1-(piperazin-1-yl)-ethanone (500 mg), n-BuOH (10 mL)and DIPEA (2 mL) were combined in a sealed tube and heated to 130° C.for 13 days. The reaction mixture was cooled, concentrated onto silicaand purified by column chromatography (SiO₂, 0-10% MeOH in EtOAc) togive a white solid. This material, MeOH (8 mL) and 2M HCl in Et₂O (4 mL)were combined and stirred at r.t. for 2 days. The reaction mixture wasconcentrated to give a yellow foam. A portion of this material (50 mg,0.12 mmol), n-BuOH (6 mL), DIPEA (1 mL) and4-chlorothieno[2,3-d]pyrimidine (50 mg, 0.25 mmol) were combined in asealed tube and heated to 130° C. for 16 h. The reaction mixture wasthen concentrated to dryness and purified by preparative HPLC to givethe title compound (19.4 mg, 32%) as a tan solid. δ_(H) (DMSO-d₆)8.40-8.30 (3H, m), 7.86 (1H, d, J 5.99 Hz), 7.78 (1H, dd, J 8.96, 6.33Hz), 7.65 (1H, d, J 5.95 Hz), 7.32 (1H, t, J 9.13 Hz), 5.84-5.75 (1H,m), 3.93-3.06 (10H, m), 2.57 (3H, s), 2.24 (61-1, s), 1.60 (3H, d, J6.69 Hz). LCMS (ES+) 508 (M+H)⁺, RT 3.51 minutes (Method 1).

Example 13 Methyl4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]-quinolin-2-yl}piperazine-1-carboxylate

A mixture of Intermediate 9 (501 mg, 1.48 mmol), methylpiperazine-1-carboxylate (981 mg, 6.80 mmol) and DIPEA (1.29 mL, 7.39mmol) in NMP (3 mL) was heated under microwave irradiation at 130° C.for 4.5 h. After cooling, the mixture was dissolved in a 1:1 mixture ofEtOAc and Et₂O (250 mL) and washed with saturated brine (3×50 mL). Theorganic layer was separated, dried (MgSO₄), filtered and concentrated invacuo. Purification by column chromatography (SiO₂, 10% EtOAc in DCM)gave a pale yellow oil (400 mg, 60%). LCMS (ES+) 447 (M+H)⁺. To this oil(400 mg, 0.896 mmol) dissolved in DCM (23 mL) was added TFA (4.1 mL).The mixture was stirred at r.t. for 1.5 h. The excess solvent wasremoved in vacuo. The oil obtained was basified with 0.2M NaOH (40 mL)and extracted with EtOAc (3×80 mL). The combined organic layers weredried (MgSO₄), filtered and concentrated in vacuo. Purification bycolumn chromatography (SiO₂, 95:4:1 DCM/MeOH/NH₃ solution in MeOH) gavea colourless gum (278 mg, 90%). LCMS (ES+) 347 (M+H)⁺. This gum (55.6mg, 0.161 mmol), 4-chlorothieno[2,3-d]pyrimidine (41.1 mg, 0.241 mmol),DIPEA (0.084 mL, 0.482 mmol) and n-BuOH (1 mL) were combined and heatedunder microwave irradiation at 130° C. for 1 h. Purification bypreparative HPLC gave the title compound (39.3 mg, 51%) as a brownglass. δ_(H) (DMSO-d₆) 8.42-8.36 (2H, m), 8.33 (1H, s), 7.86 (1H, d, J5.98 Hz), 7.78 (1H, t, J 7.56 Hz), 7.65 (1H, d, J 5.94 Hz), 7.32 (1H, t,J 9.12 Hz), 5.78 (1H, t, J 6.95 Hz), 3.74-3.62 (7H, m), 3.61-3.52 (2H,m), 3.19-3.10 (2H, m), 2.57 (3H, s), 1.58 (3H, d, J 6.64 Hz). LCMS (ES+)481 (M+H)⁺, RT 4.16 minutes (Method 2).

Example 144-{7-Fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}-N-methylpiperazine-1-carboxamide

A solution of Intermediate 9 (500 mg, 1.476 mmol),N-methylpiperazine-1-carboxamide (677 mg, 4.73 mmol) and DIPEA (1.54 mL,8.85 mmol) in NMP (3.5 mL) was heated under microwave irradiation at150° C. for 3.5 h. After cooling, the mixture was dissolved in a 1:1mixture of EtOAc and Et₂O (250 mL) and washed with saturated brine (3×50mL). The organic layer was separated, dried (MgSO₄), filtered andconcentrated in vacuo. Purification by column chromatography (SiO₂, 2%EtOAc in DCM) gave a pale yellow solid (214 mg, 33%). LCMS (ES+) 446(M+H)⁺. To this solid (214 mg, 0.48 mmol) dissolved in DCM (12 mL) wasadded TFA (2.2 mL). The reaction mixture was stirred at r.t. for 1.5 hand the excess solvent was removed in vacuo. The oil obtained wasbasified with 0.5M aqueous NaOH (20 mL) and extracted with EtOAc (3×50mL). The combined organic layers were dried (MgSO₄), filtered andconcentrated in vacuo to give a pale yellow glass (179 mg, 100%). LCMS(ES+) 346 (M+H)⁺. This material (44.7 mg, 0.129 mmol),4-chlorothieno[2,3-d]pyrimidine (33.1 mg, 0.194 mmol), DIPEA (0.068 mL,0.388 mmol) and n-BuOH (1 mL) were combined and heated under microwaveirradiation at 130° C. for 1 h. Purification by preparative HPLC gavethe title compound (2.6 mg, 4%) as a yellow solid. δ_(H) (DMSO-d₆)8.39-8.36 (2H, m), 8.33 (1H, s), 7.86 (1H, d, J 6.4 Hz), 7.80-7.76 (1H,m), 7.65 (1H, d, J 6.0 Hz), 7.32 (1H, t, J 9.2 Hz), 6.53-6.51 (1H, m),5.81-5.76 (1H, m), 3.66-3.59 (4H, m), 3.15-3.07 (4H, m), 2.63 (3H, d, J4.4 Hz), 2.57 (3H, s), 1.58 (3H, d, J 6.8 Hz). LCMS (ES+) 480 (M+H)⁺, RT3.33 minutes (Method 1).

Example 154-{7-Fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one

To a solution of Intermediate 12 (144 mg, 0.36 mmol) in DCM (5 mL) wasadded TFA (2 mL) and the mixture was allowed to stand at r.t. overnightbefore being concentrated in vacuo. The residue was dissolved in MeOHand passed through an SCX cartridge, washing with MeOH and eluting with7M NH₃ in MeOH. After concentration in vacuo, a white foam (110 mg,100%) was obtained. To this material, dissolved in n-butanol (2.9 mL)and DIPEA (0.19 mL, 1.08 mmol), was added4-chlorothieno[2,3-d]-pyrimidine (92 mg, 0.54 mmol), and the mixture washeated to 120° C. overnight in a sealed tube. The reaction mixture wasallowed to cool to r.t. and the solvent was removed in vacuo. Theresidue was redissolved in DCM (40 mL) and washed with water (20 mL) andbrine (20 mL). The organic layer was separated, dried (MgSO₄) andfiltered, and the solvent was removed in vacuo. Purification bypreparative HPLC afforded the title compound (80 mg, 51%) as a whitesolid. δ_(H) (CDCl₃) 8.41 (1H, s), 8.05 (1H, s), 7.48 (1H, dd, J 8.92,5.98 Hz), 7.38-7.28 (2H, m), 7.15 (1H, t, J 8.98 Hz), 6.82-6.76 (1H, m),5.85-5.70 (2H, m), 4.37 (1H, d, J 17.54 Hz), 4.08-3.95 (2H, m), 3.67(1H, d, J 10.18 Hz), 3.60-3.51 (1H, m), 3.43-3.36 (1H, m), 2.58 (3H, s),1.61 (3H, d, J 8.66 Hz). LCMS (ES+) 437 (M+H)⁺, RT 3.06 minutes (Method1).

Example 161-(4-{7-Fluoro-8-methyl-3-[(1S)-1-(6-methylthieno[2,3-d]pyrimidin-4-ylamino)ethyl]-quinolin-2-yl}piperazin-1-yl)ethanone

Following the procedure described for Example 4, Intermediate 11 (70 mg,0.21 mmol) and 4-chloro-6-methylthieno[2,3-d]pyrimidine (47 mg, 0.25mmol) afforded the title compound (48 mg, 48%) as a white solid. δ_(H)(DMSO-d₆) 8.31 (2H, m), 8.18 (1H, d, J 4.0 Hz), 7.78 (1H, t, J 8 Hz),7.54 (1H, s), 7.33 (1H, t, J 8 Hz), 5.77 (1H, m), 3.62-3.77 (6H, m),3.02-3.22 (2H, m), 2.59 (3H, s), 2.55 (3H, s), 2.10 (3H, s), 1.57 (3H,d, J 8 Hz). LCMS (ES+) 479 (M+H)⁺, RT 3.12 minutes (Method 2).

Example 171-(4-{7-Fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)ethanone

Following the procedure described for Example 4, Intermediate 11 (70 mg,0.21 mmol) and 4-chlorothieno[2,3-d]pyrimidine (43 mg, 0.25 mmol)afforded the title compound (40 mg, 41%) as a white solid. δ_(H)(DMSO-d₆) 8.37 (2H, m), 8.33 (1H, s), 7.86 (1H, d, J 6 Hz), 7.78 (1H, t,J 6 Hz), 7.65 (1H, d, J 6 Hz), 7.32 (1H, t, J 8 Hz), 5.81 (1H, m),3.62-3.75 (6H, m), 3.02-3.22 (2H, m), 2.57 (3H, s), 2.53 (3H, s), 1.59(3H, d, J 6.8 Hz). LCMS (ES+) 465 (M+H)⁺, RT 3.02 minutes (Method 2).

Example 181-(4-{3-[(1S)-1-(5,6-Dimethylthieno[2,3-d]pyrimidin-4-ylamino)ethyl]-7-fluoro-8-methylquinolin-2-yl}piperazin-1-yl)ethanone

Following the procedure described for Example 4, Intermediate 11 (70 mg,0.21 mmol) and 4-chloro-5,6-dimethylthieno[2,3-d]pyrimidine (47 mg, 0.25mmol) afforded the title compound (58 mg, 56%) as a white solid. δ_(H)(DMSO-d₆) 8.42 (1H, s), 8.27 (1H, s), 7.75 (1H, dt, J 2.4 and 6.4 Hz),7.32 (1H, t, J 10.6 Hz), 6.70 (1H, d, J 6.8 Hz), 5.70 (1H, m), 3.61-3.78(6H, m), 3.09-3.22 (2H, m), 2.63 (3H, s), 2.57 (3H, s), 2.47 (3H, s),2.10 (3H, s), 1.61 (3H, d, J 6.4 Hz). LCMS (ES+) 493 (M+H)⁺, RT 3.94minutes (Method 1).

1. A compound of formula (IA) or (IB) or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof:

wherein V represents O or S; Y represents N or C—R⁶; X represents N orC—R⁷; E represents an optionally substituted straight or branched C₁₋₄alkylene chain; Q represents oxygen, sulfur, N—R⁸ or a covalent bond; Mrepresents the residue of an optionally substituted saturated five-,six- or seven-membered monocyclic ring containing one nitrogen atom and0, 1, 2 or 3 additional heteroatoms independently selected from N, O andS, but containing no more than one O or S atom; W represents C—R⁹ or N;R¹, R² and R³ independently represent hydrogen, halogen, cyano, nitro,C₁₋₆ alkyl, trifluoromethyl, aryl(C₁₋₆)alkyl, hydroxy, C₁₋₆ alkoxy,difluoromethoxy, trifluoromethoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl,C₁₋₆ alkylsulfonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkyl-amino, C₂₋₆alkylcarbonylamino, C₂₋₆ alkoxycarbonylamino, C₁₋₆ alkylsulfonylamino,formyl, C₂₋₆ alkylcarbonyl, carboxy, C₂₋₆ alkoxycarbonyl, aminocarbonyl,C₁₋₆ alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, aminosulfonyl, C₁₋₆alkylaminosulfonyl or di(C₁₋₆)alkylaminosulfonyl; R⁴ represents C₁₋₆alkyl, aryl, aryl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, anyof which groups may be optionally substituted by one or moresubstituents; or hydrogen, halogen, trifluoromethyl, —OR^(a), —SR^(a),—SOR^(a), —SO₂R^(a), —NR^(b)R^(c), —NR^(c)COR^(d), —NR^(c)CO₂R^(d),—NR^(c)SO₂R^(e), —COR^(d), —CO₂R^(d), —CONR^(b)R^(c) or —SO₂NR^(b)R^(c);R⁵ and R⁶ independently represent C₁₋₆ alkyl, aryl, aryl(C₁₋₆)alkyl,heteroaryl or heteroaryl(C₁₋₆)alkyl, any of which groups may beoptionally substituted by one or more substituents; or hydrogen,halogen, trifluoromethyl, —OR^(a), —SR^(a), —SOR^(a), —SO₂R^(a),—NR^(b)R^(c), —NR^(c)COR^(d), —NR^(c)CO₂R^(d), —NR^(c)SO₂R^(e),—COR^(d), —CO₂R^(d), —CONR^(b)R^(c) or —SO₂NR^(b)R^(c); or R⁵ and R⁶,when taken together with the carbon atoms to which they are attached,represent optionally substituted C₅₋₇ cycloalkenyl; R⁷ represents C₁₋₆alkyl, aryl, aryl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, anyof which groups may be optionally substituted by one or moresubstituents; or hydrogen, halogen, trifluoromethyl, —OR^(a), —SR^(a),—SOR^(a), —SO₂R^(a), —NR^(b)R^(c), —NR^(c)COR^(d), —NR^(c)CO₂R^(d),—NR^(c)SO₂R^(e), —COR^(d), —CO₂R^(d), —CONR^(b)R^(c) or —SO₂NR^(b)R^(c);R⁸ represents hydrogen or C₁₋₆ alkyl; R⁹ represents hydrogen, halogen,C₁₋₆ alkyl or C₁₋₆ alkoxy; R^(a) represents C₁₋₆ alkyl, difluoromethylor trifluoromethyl; R^(b) represents hydrogen or trifluoromethyl; orC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl,aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl-(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, anyof which groups may be optionally substituted by one or moresubstituents; R^(c) represents hydrogen, C₁₋₆ alkyl or C₃₋₇ cycloalkyl;R^(d) represents hydrogen or C₁₋₆ alkyl; and R^(e) represents C₁₋₆alkyl.
 2. A compound as claimed in claim 1 represented by formula (IIA)or an N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof:

wherein E, Q, M, R¹, R², R⁵ and R⁶ are as defined in claim
 1. 3. Acompound as claimed in claim 1 represented by formula (IIB) or anN-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof:

wherein E, Q, M, R¹, R², R⁵ and R⁶ are as defined in claim
 1. 4. Acompound as claimed in claim 1 wherein M represents the residue of amonocyclic ring selected from pyrrolidin-1-yl, piperidin-1-yl andpiperazin-1-yl, any of which rings may be optionally substituted by oneor more substituents independently selected from oxo, C₂₋₆alkylcarbonyl, hydroxy(C₁₋₆)alkyl-carbonyl,di(C₁₋₆)alkylamino(C₁₋₆)alkylcarbonyl, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl, hydroxy(C₁₋₆)alkylcarbonylamino,(C₃₋₇)cycloalkylcarbonylamino, aminocarbonyl and C₁₋₆alkylaminocarbonyl.
 5. A compound as claimed in claim 1 wherein themoiety of which M is the residue is selected from3-(hydroxyacetylamino)pyrrolidin-1-yl,3-(cyclopropylcarbonylamino)pyrrolidin-1-yl, 4-carboxypiperidin-1-yl,4-(aminocarbonyl)-piperidin-1-yl, 3-oxopiperazin-1-yl,4-acetylpiperazin-1-yl, 4-(hydroxyacetyl)piperazin-1-yl,4-(dimethylaminoacetyl)piperazin-1-yl, 4-(carboxymethyl)piperazin-1-yl,4-(methoxycarbonyl)piperazin-1-yl and4-(methylaminocarbonyl)piperazin-1-yl.
 6. A compound as claimed in claim1 wherein E represents methylene or (methyl)methylene.
 7. A compound asclaimed in claim 1 wherein Q represents N—R⁸, in which R⁸ is as definedin claim
 1. 8. A compound as claimed in claim 1 wherein R¹ representshydrogen, halogen or C₁₋₆ alkyl.
 9. A compound as claimed in claim 1wherein R² represents hydrogen or halogen.
 10. A compound as claimed inclaim 1 wherein R⁵ represents hydrogen or C₁₋₆ alkyl.
 11. A compound asclaimed in claim 1 wherein R⁶ represents hydrogen or C₁₋₆ alkyl.
 12. Acompound selected from the group consisting of(S)-4-{8-chloro-3-[1-(7-methylthieno[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one;(S)-4-{8-chloro-3-[1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one;(S)-4-{8-chloro-3-[1-(6-methylthieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one;(S)-1-(4-{3-[1-(2,3-dihydro-1H-8-thia-5,7-diazacyclopenta[a]inden-4-ylamino)ethyl]-7-fluoro-8-methylquinolin-2-yl}piperazin-1-yl)ethanone;N-[(3R)-1-{8-chloro-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}pyrrolidin-3-yl]-2-hydroxyacetamide;(4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)aceticacid;1-(4-{8-chloro-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)-2-hydroxyethanone;1-(4-{8-chloro-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)-2-(dimethylamino)ethanone;1-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperidine-4-carboxamide;1-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperidine-4-carboxylicacid;N-[(3S)-1-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]-quinolin-2-yl}pyrrolidin-3-yl]cyclopropanecarboxamide;2-(dimethylamino)-1-(4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)ethanone;methyl4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]-quinolin-2-yl}piperazine-1-carboxylate;4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}-N-methylpiperazine-1-carboxamide;4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one;1-(4-{7-fluoro-8-methyl-3-[(1S)-1-(6-methylthieno[2,3-d]pyrimidin-4-ylamino)ethyl]-quinolin-2-yl}piperazin-1-yl)ethanone;1-(4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)ethanone;1-(4-{3-[(1S)-1-(5,6-dimethylthieno[2,3-d]pyrimidin-4-ylamino)ethyl]-7-fluoro-8-methylquinolin-2-yl}piperazin-1-yl)ethanone;and a pharmaceutically acceptable salt, solvate, or N-oxide of any ofthe foregoing.
 13. A compound of formula (I) as defined in claim 1 or anN-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof, for use in therapy.
 14. A compound of formula (I) as defined inclaim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof, for use in the treatment and/or prevention of adisorder for which the administration of a selective PI3K inhibitor isindicated.
 15. A pharmaceutical composition comprising a compound offormula (I) as defined in claim 1 or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof, in association witha pharmaceutically acceptable carrier.
 16. The use of a compound offormula (I) as defined in claim 1 or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof, for the manufactureof a medicament for the treatment and/or prevention of a disorder forwhich the administration of a selective PI3K inhibitor is indicated. 17.A method for the treatment and/or prevention of a disorder for which theadministration of a selective PI3K inhibitor is indicated whichcomprises administering to a patient in need of such treatment aneffective amount of a compound of formula (I) as defined in claim 1 oran N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.